Project Summary/Abstract The overall goal of this research is to quantify the cross-sectional associations between measured and modeled perfluoroalkyl and polyfluoroalkyl substances (PFAS) in highly exposed adults and children and selected health outcomes, including lipids, kidney function, liver function, thyroid hormones and sex hormones, glucose and insulin parameters, markers of immune function, and neurobehavioral outcomes in children. We will enroll 1,000 adults and 400 children from a community in El Paso County, Colorado who experienced high levels of PFAS contamination of their municipal drinking water and private wells resulting from the use of aqueous film-forming foams (AFFF) for firefighting activities at a nearly US Air Force Base. Exposure to PFAS will be assessed via measured serum concentrations and through a detailed model to reconstruct historical PFAS concentrations in groundwater and drinking water in El Paso County. Combining this information with individual residential histories, we will be able to estimate cumulative lifetime exposure to AFFF-related PFAS in El Paso County for each study participant. Our research team is well qualified to achieve this goal due to our complementary expertise in exposure science (Adgate), environmental epidemiology (Starling), PFAS chemistry and drinking water exposure (Higgins, Vestergren), groundwater modeling (Singha, McCray), neurobehavioral testing (Wilkening), cancer epidemiology (Cockburn), statistical methods for the analysis of observational data (Glueck), and community outreach and education (Richardson, Celico). We have conducted a pilot study in El Paso County that demonstrates the feasibility of recruiting participants to complete study procedures similar to those in the ATSDR protocol. The preliminary results of our pilot study show: (1) a unique AFFF-related exposure profile with median concentrations of perfluorohexane sulfonate (PFHxS) more than ten times the median of the general US population, and (2) prominent differences in AFFF-related PFAS exposure by geographic area with an apparent north-south gradient in serum concentrations within El Paso County. In addition to the common core protocol, we propose two investigator-initiated aims: (1) a highly innovative examination of the association between PFAS and biomarkers linked to testicular and thyroid cancer risk (both previously identified in human and animal studies as potentially related to PFAS exposure), and (2) the application of novel statistical methods to estimate the combined effect of exposure to the complex mixture of PFAS found in AFFF-contaminated drinking water, and to separate the effects of individual PFAS from the correlated mixture. This research fills an important knowledge gap because populations in numerous US states have been exposed to AFFF-derived PFAS via contaminated drinking water. The completion of these aims will provide essential information for communities, researchers, and policymakers seeking to understand the health risks associated with this emerging PFAS exposure profile.